.omega.-Aminoalkanoic acids have a wide variety of applications. One such use is as spacer molecules in solid phase peptide synthesis (SPPS). These spacer molecules serve to distance the growing peptide chains from the solid resin support allowing the supported biopolymers to be more accessible for subsequent chemical reactions. J. Org. Chem., 41, page 1350, (1976). Incorporation of such spacers can be important in the preparation of combinatorial libraries wherein large enzymes or antibodies are frequently used to assess the in-vitro activities of the pendant peptides. Minimization of restrictions exerted by the resin allows a more effective interaction between the protein and peptide, Immunomethods, 1, page 11, (1992).
For example, substituted 6-aminocaproic acid derivatives have been used to induce and maintain conformational rigidity in peptide fragments. The resulting cyclic peptidomimetic compounds have .beta.-turn structures. J. Am. Chem., 117, page 5169, (1995).
The .omega.-aminoalkanoic acids are also used in the covalent modification of antigenic peptides with lipophilic moieties such as aminohexadecanoic acid or lauric acid to enhance immunogenicity. For example, a laurylpetide adjuvant can be coupled to a 16 amino acid peptide from the V3 loop of the third hypervariable domain of the HIV-1 to envelope glycoprotein gp 120. This adjuvant-linked peptide stimulated elevated immune responses when compared to the peptide alone. J. Med. Chem., 38, page 459, (1995).
The .omega.-aminoalkanoic acids can also serve as useful synthetic "handles" for these adjuvants since these acids contain both amino and carboxylic termini which can be further derivatized.
Because of the many uses for .omega.-aminoalkanoic acids, there is a need in the art for a simple, inexpensive route to prepare these .omega.-aminoalkanoic acids and their derivatives. A number of methods for the preparations of .omega.-aminoalkanoic acids have been reported. The amine group on the .omega.-aminoalkanoic acids can be introduced by first converting a ketone to an oxime using hydroxylamine sulfonic acid. The .omega.-hydroxyimino acids formed are then reduced using Raney nickel to provide .omega.-aminoalkanoic acids. (French Patent 1,349,281, Jan. 7, 1964). The preparation of .omega.-aminoalkanoic acids by reduction of an organic acid with a terminal nitrile to an amine, with lithium aluminum hydride, has also been reported. The nitriles were prepared by conversion of an acid having a terminal group such as a halogen to a nitrile group. Chem. Tech., 8, page 187, (1956). Other methods require formation of an anhydride from an organic diacid followed by opening the anhydride with an azide. The intermediate compound was rearranged via a Schmidt rearrangement at an elevated temperature (50-60.degree.). Chem & Pharm. Bull., 7, page 99, (1959). Cyclic anhydrides have been opened with concentrated ammonium hydroxide followed by warming to about 50.degree. and addition of sodium hydroxide to provide the corresponding half amide. The half-amide can be converted to the corresponding .omega.-aminoalkanoic acid by Hofmann rearrangement using aqueous base and bromine. Chem. Ber., 89, page 117, (1956).
Boc protected .omega.-aminoalkanoic acids have been prepared from lactams that have been previously acylated with a t-butyloxycarbonyl acylating agent. The N-acylated lactam product can be treated with a base in aqueous tetrahydrofuran to provide the N-butoxycarbonyl .omega.-aminoalkanoic acids by hydrolysis. However, chromatographic purification of the N-butoxycarbonyl lactams is usually required. J. Org. Chem., 48, page 2424, (1983).
Aube et al. recently reported the synthesis Boc protected peptides of methyl substituted 6-aminohexanoic acid. A lactam was prepared and opened with hydrochloric acid solution. The ring opened lactam can be coupled to the peptide. However, this procedure required protection of the carboxyl terminus of the 6-aminohexanoic acids as a methyl esters before coupling with the peptide. J. Med. Chem., 117, page 5169, (1995).
Each of the preceding methods have difficulties such as low yields, the need for purification, expensive reagents and/or scale-up problems.